Adverse effects of RBC transfusions: A unifying hypothesis

描述（由申请人提供）：输血红细胞（rbc）是美国医院最常见的治疗方法，通常可有效预防贫血患者的发病率和死亡率。然而，最近的研究表明，一些红细胞单位存在功能缺陷，损害了它们的功效，实际上可能对输血患者造成伤害。这些缺陷，表现为输血前红细胞储存时间的延长，被称为“红细胞储存损伤”。每年有成千上万的患者因红细胞储存损伤而输血，但目前我们还没有准确的方法来识别这种单位。在之前的R01资助期间，我们在血库储存期间观察到意想不到的献血者对献血者的红细胞代谢差异。基于这些数据，我们建议确定特定的代谢（人类红细胞）和遗传（小鼠红细胞）生物标志物，这些生物标志物不仅反映了由于储存时间和/或供体因素导致的红细胞功能的潜在差异，而且还可以在临床上用于预测哪些红细胞单位可能导致输血后不良事件，从而在输血前将其从血液供应中移除。为了提供最有力的方法来实现这一目标，我们提出了一项综合研究工作，结合(1)基于供体/受体的人类红细胞输血研究的相关性，以及(2)小鼠模型的机制能力。人体研究将利用我们开发的方法来识别代谢生物标志物，预测红细胞功能、输血后红细胞存活和血管效应。小鼠研究的优势包括精细的遗传特征，快速的繁殖时间，容易产生复杂的谱系，以及表型-基因型分析的能力。这些优势将通过执行GWAS来识别小鼠红细胞储存表型的遗传标记，然后选择性回交来确定所选遗传元件与感兴趣表型之间的因果关系。拟议的协调调查允许每个模型用于其独特的优势，同时补偿内在的弱点，从而提供了所选生物标志物的有效交叉验证。这些研究将延长之前资助期开始的工作，并将导致RBC生物标记物的验证，我们相信这些标记物将识别最可能导致不良受体效应的RBC单位，使它们在输血前被隔离。

DESCRIPTION (provided by applicant): Transfusion of red blood cells (RBCs), the most common therapeutic procedure performed in US hospitals, is usually effective at preventing morbidity and mortality in anemic patients. However, recent studies indicate that some RBC units have functional defects that impair their efficacy and may actually cause harm to transfused patients. These defects, which appear to increase the longer RBC units are stored prior to transfusion, have been called "RBC storage lesions". Transfusion of RBC units with storage lesions may adversely affect thousands of patients annually, but at present we have no accurate methods to identify such units. During the previous funding period for this R01 grant, we observed unexpected donor-to-donor variability in RBC metabolism during blood bank storage. Based on these data, we propose to identify specific metabolic (human RBCs) and genetic (murine RBCs) biomarkers that not only reflect the underlying differences in RBC function due to storage time and/or donor factors, but also can be used clinically to predict which RBC units may cause adverse post-transfusion events, allowing them to be removed from the blood supply before transfusion. To provide the most powerful approach to achieve this goal, we propose an integrated research effort that combines (1) the relevancy of donor/recipient-based human RBC transfusion investigations, with (2) the mechanistic power of mouse models. The human studies will utilize methodologies we have developed to identify metabolic biomarkers that predict RBC function, post-transfusion RBC survival, and vascular effects. The advantages of mouse studies include finely characterized genetics, rapid breeding times, ease of generating complex pedigrees, and the power of phenotype-genotype analysis. These advantages will be exploited by performing GWAS to identify genetic markers for mouse RBC storage phenotypes, and then selectively backcrossing to establish causality between selected genetic elements and phenotypes of interest. The proposed coordinated investigations allow each model to be used for its unique strengths, while compensating for intrinsic weaknesses, and thus provides efficient cross- validation of selected biomarkers. These studies will extend work started during the previous funding period, and will lead to the validation of RBC biomarkers that we believe will identify RBC units most likely to cause adverse recipient effects, allowing them to be sequestered prior to transfusion.